Phase 3 Trial of Blinatumomab vs Standard Chemotherapy in Pediatric Subjects With HIgh-Risk (HR) First Relapse B-precursor Acute Lymphoblastic Leukemia (ALL)

Phase 3 Trial to Investigate the Efficacy, Safety, and Tolerability of Blinatumomab as Consolidation Therapy Versus Conventional Consolidation Chemotherapy in Pediatric Subjects With HR First Relapse B-precursor ALL

B-precursor ALL is an aggressive malignant disease. Therapy is usually stratified according to risk characteristics to ensure that appropriate treatment is administered to patients with high-risk of relapse. In general, pediatric treatment regimens are more intense than those employed in adults and include courses of combination chemotherapy. Standard of care chemotherapy is associated with considerable toxicity. There is a lack of novel treatment options for subjects who relapse or are refractory to treatment. Therefore, innovative therapeutic approaches are urgently needed. Blinatumomab is a bispecific single-chain antibody construct designed to link B cells and T cells resulting in T cell activation and a cytotoxic T cell response against CD19 expressing cells. This study will evaluate the event-free survival (EFS) after treatment with blinatumomab when compared to standard of care (SOC) chemotherapy. The effect of blinatumomab on overall survival and reduction of minimal residual disease compared to SOC chemotherapy will also be investigated.

Patients will be randomized in a 1:1 ratio to receive either one cycle of blinatumomab or one block of standard high-risk consolidation chemotherapy. Blinatumomab is administered as a continuous intravenous infusion (CIVI). One cycle of blinatumomab treatment includes 4 weeks of CIVI of blinatumomab. After completing consolidation therapy, the patients should undergo alloHSCT depending on their bone marrow status. The patients will be followed up until the last subject on study is 36 months following alloHSCT or has died, whichever is first.

Inclusion Criteria:

• Subjects with Philadelphia chromosome negative (Ph-) high-risk (HR) first relapse B-precursor acute lymphoblastic leukemia (ALL; as defined by International Berlin-Frankfurt-Muenster study group/International study for treatment of childhood relapsed ALL [I-BFM SG/IntReALL] criteria)
• Subjects with bone marrow blast percentage < 5% (M1) or bone marrow blast percentage < 25% and ≥5% (M2) marrow at the time of randomization,
• Age > 28 days and < 18 years at the time of informed consent/assent
• Subject's legally acceptable representative has provided informed consent when the subject is legally too young to provide informed consent and the subject has provided written assent based on local regulations and/or guidelines prior to any study-specific activities/procedures being initiated
• Availability of the following material from relapse diagnosis for central analysis of minimal residual disease (MRD) by polymerase chain reaction (PCR): clone-specific primers and reference deoxyribonucleic acid (DNA), as well as primer sequences and analyzed sequences of clonal rearrangements (cases with isolated extramedullary relapse or cases with technical and/or logistic hurdles to obtain and process bone marrow material are exempt from providing this material. In these cases, central MRD analysis only by Flow is permitted).

Exclusion Criteria:

• Clinically relevant central nervous system (CNS) pathology requiring treatment (eg, unstable epilepsy). Evidence of current CNS (CNS 2, CNS 3) involvement by ALL. Subjects with CNS relapse at the time of relapse are eligible if CNS is successfully treated prior to enrollment
• Peripheral neutrophils < 500/μL prior to start of treatment
• Peripheral platelets < 50,000/μL prior to start of treatment
• Currently receiving treatment in another investigational device or drug study or less than 4 weeks since ending treatment on another investigational device or drug study(s), procedures required by IntReALL high-risk (HR) guidelines are allowed
• Chemotherapy related toxicities that have not resolved to ≤ grade 2 (except for parameters defined in Exclusion Criteria 202, 203, 204, and 217)
• Symptoms and/or clinical signs and/or radiological and/or sonographic signs that indicate an acute or uncontrolled chronic infection, any other concurrent disease or medical condition that could be exacerbated by the treatment or would seriously complicate compliance with the protocol
• Abnormal renal or hepatic function prior to start of treatment (day 1) as defined below
• Abnormal serum creatinine based on age/gender
• Total bilirubin > 3.0 mg/dL prior to start of treatment (unless related to Gilbert's or Meulengracht disease)
• Documented infection with human immunodeficiency virus (HIV)
• Known hypersensitivity to immunoglobulins or any of the products or components to be administered during dosing (excluding asparaginase)
• Post-menarchal female subject who is pregnant or breastfeeding, or is planning to become pregnant or breastfeed while receiving protocol-specified therapy and for at least 12 months after the last dose of chemotherapy
• Post-menarchal female subject who is not willing to practice true sexual abstinence or use a highly effective form of contraception while receiving protocol-specified therapy and for at least 12 months after the last dose of chemotherapy
• Sexually mature male subject who is not willing to practice true sexual abstinence or use a condom with spermicide while receiving protocol-specified therapy and for at least 6 months after last dose of chemotherapy. In countries where spermicide is not available, a condom without spermicide is acceptable
• Sexually mature male subject who is not willing to abstain from sperm donation while receiving protocol-specified therapy and for at least 6 months after last dose of chemotherapy
• Subject likely to not be available to complete all protocol-required study visits or procedures, including follow-up visits, and/or to comply with all required study procedures to the best of the subject's and investigator's knowledge
• History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures, or completion
• Placed into an institution due to juridical or regulatory ruling.